Effects of leucovorin on the pharmacokinetics of methotrexate in rabbits

Dose-independent pharmacokinetics of oltipraz after intravenous and/or oral administration at various doses to mice, rats, rabbits and dogs were evaluated. After both intravenous and/or oral administration of oltipraz to mice (5, 10 and 20 mg/kg for intravenous and 15, 30 and 50 mg/kg for oral administration), rats (5, 10 and 20 mg/kg for intravenous and 25, 50 and 100 mg/kg for oral administration), rabbits (5, 10 and 30 mg/kg for intravenous administration) and dogs (5 and 10 mg/kg for intravenous and 50 and 100 mg/kg for oral administration), the total area under the plasma concentration-time curve from time zero to time infinity (AUC) values of oltipraz were dose-proportional in all animals studied. Animal scale-up of some pharmacokinetics parameters of oltipraz was also performed based on the parameters after intravenous administration at a dose of 10 mg/kg to mice, rats, rabbits and dogs. Linear relationships were obtained between log time-averaged total body clearance (Cl) x maximum life-span potential (MLP) (1 year/h) and log species body weight (W) (kg) (r=0.999; p=0.0015), log Cl (l/h) and log W (kg) (r=0.979; p=0.0209), and log apparent volume of distribution at steady state (V(ss)) (l) and log W (kg) (r=0.999; p=0.0009). The corresponding allometric equations were ClxMLP=49.8 W(0.861), Cl=5.20 W(0.523) and V(ss)=4.46 W(0.764). Interspecies scale-up of plasma concentration-time data for the four species using pharmacokinetic time of dienetichron resulted in similar profiles. In addition, concentrations of oltipraz in a plasma concentration-time profile for humans predicted using the four animal data fitted to the dienetichron time transformation of animal data.

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Interspecies pharmacokinetic scaling of oltipraz in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics

Bae

Lee

Kim

et al. 2005

Biopharm & Drug Disp

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Species differences in the formation of DA-8164 after intravenous and/or oral administration of DA-8159, a new erectogenic, to mice, rats, rabbits, dogs and humans

Shim

Kim

Lee

et al. 2005

Biopharm. Drug Dispos.

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Species differences in the formation of DA-8164 after intravenous and/or oral administration of DA-8159 to mice, rats, rabbits, dogs and humans were investigated. After intravenous administration of DA-8159, the formation of DA-8164 decreased in the order mice, rats, rabbits and dogs; the AUC(DA-8164)/AUC(DA-8159) ratios were 0.479, 0.199, 0.0452 and close to 0 (DA-8164 was below the detection limit in dog plasma), respectively. After oral administration of DA-8159, the formation of DA-8164 was considerable in mice, rats and humans, but almost negligible in dogs; the AUC (or AUC(0-t))(DA-8164)/AUC (or AUC(0-t))(DA-8159) ratios were 2.99, 2.67, 1.39 and 0.0650, respectively. The above data suggested that the formation of DA-8164 was almost negligible after both intravenous and oral administration in dogs. The species differences for the formation of DA-8164 may be due to the involvement of different CYP isozymes for each species and/or a different amount or activity of CYP isozyme if the same CYP isozyme is involved for the formation of DA-8164 for all species. The AUC (or AUC(0-t))(DA-8164)/AUC (or AUC(0-t))(DA-8159) ratios after oral administration were greater than those after intravenous administration in mice, rats and dogs, and this could be due to considerable first-pass (gastric, intestinal and/or hepatic) effects in the species as proved in rats.

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Interspecies pharmacokinetic scaling of DA-8159, a new erectogenic, in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics

Shim¹,

Kim²,

Lee³

et al. 2005

Biopharm. Drug Dispos.

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Time-averaged total body clearance (Cl) and apparent volume of distribution at steady state (V(SS)) of DA-8159 after intravenous administration to mice (30 mg/kg), rats (30 mg/kg), rabbits (30 mg/kg) and dogs (3 mg/kg) were analysed as a function of species body weight (W) using the allometric equation for interspecies scaling, and were used to predict those in humans. Significant linear relationships were obtained between log Cl (l/h) and log W (kg) (r = 0.992; p = 0.0079) and log V(SS) (l) and log W (kg) (r = 0.999; p < 0.0001). The corresponding allometric equations were Cl = 4.36 W(0.492) and V(SS) = 6.41 W(0.911). These allometric equations were extrapolated to predict the Cl and V(SS) for DA-8159 in humans based on the 70 kg body weights. In addition, concentrations in the plasma-time profile predicted using the four animal data fitted to a complex Dedrick plot of animal data. Our results indicated that the DA-8159 data obtained from four laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters in humans. These parameters can serve as guidelines for better planning of clinical studies.

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Effects of leucovorin on the pharmacokinetics of methotrexate in rabbits

Cited by 4 publications

References 11 publications

Interspecies pharmacokinetic scaling of oltipraz in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics

Interspecies pharmacokinetic scaling of oltipraz in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics

Species differences in the formation of DA-8164 after intravenous and/or oral administration of DA-8159, a new erectogenic, to mice, rats, rabbits, dogs and humans

Interspecies pharmacokinetic scaling of DA-8159, a new erectogenic, in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics

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